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1.
Ecotoxicol Environ Saf ; 226: 112851, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34619480

RESUMO

Long-term excessive intake of fluoride (F) can cause osseous and non-osseous damage. The kidney is the main fluoride excretion organ of the body. This study aimed to explore whether dietary calcium (Ca) supplementation can alleviate kidney damage caused by fluorosis and to further investigate the effects of Ca on the mitigation mechanism of renal cell apoptosis triggered by F. We evaluated the histopathological structure, renal function indicators, and gene and protein expression levels of death receptor-mediated apoptosis pathways in Sprague Dawley (SD) rats treated with sodium fluoride (NaF) and/or calcium carbonate (CaCO3) for 120 days. The results showed that 100 mg/L NaF induced kidney histopathological injury and apoptosis, increased the concentrations of Creatinine (CRE), uric acid (UA), blood urea nitrogen (BUN), potassium (K), phosphorus (P) and F (p < 0.05), and decrease the level of serum magnesium (Mg) (p < 0.05). Moreover, NaF increased the mRNA and protein expression levels of Fas cell surface death receptor (FAS), tumor necrosis factor (TNF), TNF-related apoptosis-inducing ligand (TRAIL), Caspase 8, Caspase 3 and poly ADP-ribose polymerase (PARP) (p < 0.01), which finally activated the death receptor pathway. Inversely, Ca supplementation reversed the decrease of CRE, BUN, UA, F and P levels induced by F, alleviated histopathological damage and apoptosis, and reduced the gene and protein expression levels of death receptor pathway-related markers. In conclusion, 1% Ca alleviates F-induced kidney apoptosis through FAS/FASL, TNFR/TNF, DR5/TRAIL signaling pathways.

2.
Toxicol Res (Camb) ; 10(4): 911-927, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34484683

RESUMO

Cholestasis is a severe clinical complication that severely damages the liver. Kidneys are also the most affected extrahepatic organs in cholestasis. The pivotal role of oxidative stress has been mentioned in the pathogenesis of cholestasis-induced organ injury. The activation of the nuclear factor-E2-related factor 2 (Nrf2) pathway is involved in response to oxidative stress. The current study was designed to evaluate the potential role of Nrf2 signaling activation in preventing bile acids-induced toxicity in the liver and kidney. Dimethyl fumarate was used as a robust activator of Nrf2 signaling. Rats underwent bile duct ligation surgery and were treated with dimethyl fumarate (10 and 40 mg/kg). Severe oxidative stress was evident in the liver and kidney of cholestatic animals (P < 0.05). On the other hand, the expression and activity of Nrf2 and downstream genes were time-dependently decreased (P < 0.05). Moreover, significant mitochondrial depolarization, decreased ATP levels, and mitochondrial permeabilization were detected in bile duct-ligated rats (P < 0.05). Histopathological alterations included liver necrosis, fibrosis, inflammation and kidney interstitial inflammation, and cast formation. It was found that dimethyl fumarate significantly decreased hepatic and renal injury in cholestatic animals (P < 0.05). Based on these data, the activation of the cellular antioxidant response could serve as an efficient therapeutic option for managing cholestasis-induced organ injury.

3.
Sci Total Environ ; 804: 150184, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34517333

RESUMO

As an environmental toxicant, the damage of fluoride to the body has attracted global attention. Because liver is an essential organ for fluoride accumulation and damage. Our previous studies revealed fluoride-induced hepatic injury through interleukin 17A (IL-17A) pathway, but the underlying cellular mechanism remains unclear. Hence, this research explored the mechanism of IL-17A pathway and mitophagy in fluoride-induced liver injury through the use of the mice fluorosis model, IL-17A addition fluorosis cell model, IL-17A gene knockout mice fluorosis model, flow cytometry, immunohistochemistry, fluorescence double staining, ELISA, western blotting, and other techniques. The results showed that fluoride reduced the bodyweight and liver coefficient, increased the bone fluoride content, the aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GDH) levels, caspase 8 and caspase 9 activities, and induced liver morphology and ultrastructure damage. Furthermore, the protein expression levels of IL-17A pathway key proteins, IL-17A, IL-17R, and Act1 were increased, but IκB was decreased after fluoride exposure. In addition, fluoride exposure elevated the mitochondrial depolarization percent, the mitochondria damage, the fluorescent spots of mitophagy, and the LC3II/LC3I protein relative expression level. To further verify the role of the IL-17A pathway in fluoride-induced hepatocyte mitochondrial damage and mitophagy disorder, the IL-17A was added and knocked out in cells of animals. The results showed that the addition of IL-17A aggravated fluoride-induced liver morphology and functional damage, activation of the IL-17A pathway, mitochondrial injury, and mitophagy, but the IL-17A knockout mitigated fluoride-induced changes. These results suggested that fluoride exposure induced mitochondrial damage and mitophagy through the IL-17A pathway in hepatocytes.

4.
Toxicol Lett ; 349: 12-29, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34089816

RESUMO

The cholestatic liver injury could occur in response to a variety of diseases or xenobiotics. Although cholestasis primarily affects liver function, it has been well-known that other organs such as the kidney could be influenced in cholestatic patients. Severe cholestasis could lead to tissue fibrosis and organ failure. Unfortunately, there is no specific therapeutic option against cholestasis-induced organ injury. Hence, finding the mechanism of organ injury during cholestasis could lead to therapeutic options against this complication. The accumulation of potentially cytotoxic compounds such as hydrophobic bile acids is the most suspected mechanism involved in the pathogenesis of cholestasis-induced organ injury. A plethora of evidence indicates a role for the inflammatory response in the pathogenesis of several human diseases. Here, the role of nuclear factor-kB (NFkB)-mediated inflammatory response is investigated in an animal model of cholestasis. Bile duct ligated (BDL) animals were treated with sulfasalazine (SSLZ, 10 and 100 mg/kg, i.p) as a potent inhibitor of NFkB signaling. The NFkB proteins family activity in the liver and kidney, serum and tissue levels of pro-inflammatory cytokines, tissue biomarkers of oxidative stress, serum markers of organ injury, and the liver and kidney histopathological alterations and fibrotic changes. The oxidative stress-mediated inflammatory-related indices were monitored in the kidney and liver at scheduled time intervals (3, 7, and 14 days after BDL operation). Significant increase in serum and urine markers of organ injury, besides changes in biomarkers of oxidative stress and tissue histopathology, were evident in the liver and kidney of BDL animals. The activity of NFkB proteins (p65, p50, p52, c-Rel, and RelB) was significantly increased in the liver and kidney of cholestatic animals. Serum and tissue levels of pro-inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-7, IL-12, IL-17, IL-18, IL-23, TNF-α, and INF-γ) were also higher than sham-operated animals. Moreover, TGF- ß, α-SMA, and tissue fibrosis (Trichrome stain) were evident in cholestatic animals' liver and kidneys. It was found that SSLZ (10 and 100 mg/kg/day, i.p) alleviated cholestasis-induced hepatic and renal injury. The effect of SSLZ on NFkB signaling and suppression of pro-inflammatory cytokines could play a significant role in its protective role in cholestasis. Based on these data, NFkB signaling could receive special attention to develop therapeutic options to blunt cholestasis-induced organ injury.


Assuntos
Anti-Inflamatórios/farmacologia , Colestase/tratamento farmacológico , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Sulfassalazina/farmacologia , Animais , Colestase/metabolismo , Colestase/patologia , Ducto Colédoco/cirurgia , Modelos Animais de Doenças , Regulação para Baixo , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Ligadura , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais
6.
Biol Trace Elem Res ; 199(5): 1919-1928, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32710350

RESUMO

For this study, we investigate more deeply the effect calcium (Ca) develops on the mechanism underlying fluoride-triggered osteocyte apoptosis. We detected the morphology of osteocytes by HE staining, mitochondrial microstructure by using the transmission electron microscope, and the biochemical indexes related to bone metabolism and the expression of apoptosis-related genes. These results showed that NaF brought out the reduced osteocytes and ruptured mitochondrial outer membrane, with a significantly increased StrACP activity by 10.414 IU/L at the 4th week (P < 0.05), markedly upregulating the mRNA expression of Bax, Cyto-C, Apaf-1, caspase-7, ROCK-1, BMP-2, and BGP (P < 0.01), as well as caspase-6 (P < 0.05), while downregulating Bcl-2 by 61.3% (P < 0.01). Through immunohistochemical analysis, we also found that NaF notably increased the protein expression of ROCK-1 (P < 0.05) and Cyto-C, BMP-2, and BGP (P < 0.01), suggesting that NaF triggered the activation of the mitochondrial apoptotic pathway and Rho/ROCK signaling pathway. Nevertheless, 1% Ca supplementation in diet notably enhanced the mRNA expression of Bcl-2 by 39.3% (P < 0.01), thus blocking the increment of the expression of mitochondrial apoptotic pathway-related genes and ROCK-1. Meanwhile, Ca could attenuate the StrACP activity by 10.741 IU/L at the 4th week (P < 0.05) and protect the integrity of the mitochondrial outer membrane. These findings strongly suggest that 1% Ca abated the mitochondrial apoptosis pathway by increasing the anti-apoptotic gene Bcl-2 expression, and effectively inhibited the hyper-activation of ROCK-1, dually protecting the structural integrity of the mitochondrial outer membrane and maintaining normal cellular metabolic function.


Assuntos
Cálcio , Intoxicação por Flúor , Animais , Apoptose , Mitocôndrias , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteína X Associada a bcl-2
7.
Toxicol In Vitro ; 72: 105074, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33352257

RESUMO

Arsenic (As), a potent toxicant, is known to be a hepatotoxicant. Although As induced liver apoptosis and autophagy, the relationship between apoptosis and autophagy of hepatocytes caused by As remains largely unknown. 3-methyladenine (3-MA) and rapamycin can inhibit and promote autophagy of AML-12 cells, respectively. Hence, in this study, AML-12 cells were treated with different concentrations (0, 2, 4, 6, 8, 10 and 12 µmol/L) of As2O3, and 5 mmol/L 3-MA or 100 nmol/L rapamycin were applied to distinguish the effect of autophagy on apoptosis in AML-12. Results showed that exposure to As induced cell apoptosis and autophagy, which were mediated by the significantly altered expression levels of autophagy markers (mTOR, LC3, PI3K and P62), and apoptosis markers (Bcl-2 and caspase-3). Further analysis indicated that a certain dosage of 3-MA and rapamycin decreased apoptosis and the caspase-3 expression, which suggested that As-induced autophagy regulated AML-12 cells apoptosis through the expressions of PI3K, mTOR, P62 and Bcl-2.


Assuntos
Apoptose/efeitos dos fármacos , Trióxido de Arsênio/toxicidade , Autofagia/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Sirolimo/farmacologia
8.
Sci Total Environ ; 742: 140533, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-32721723

RESUMO

Increasing investigations suggest that fluoride (F) exposure was associated with gastrointestinal diseases, but related literatures were still largely insufficient and the underlying mechanisms have not been fully elucidated. Moreover, previous study in our lab reported F toxicity has the reversible tendency, but it still needs to be further explored. To address this issue, we established a 90 days F exposure and 15 days & 30 days self-recovery mice model, including control and three F groups (25, 50 and 100 mg/L sodium fluoride (NaF)) in each period. The results revealed that after 90 days F exposure, histological structure and ultrastructure of small intestine were markedly disrupted; the value of villus height to crypt depth, and expressions of tight junctions related mRNA and proteins were significantly decreased; intestinal permeability, pro-inflammatory cytokines and pyroptosis related mRNA and proteins were notably increased in duodenum, jejunum and ileum. However, intriguingly, after 30 days recovery period, indices in F groups almost all have recovered towards normalcy. Collectively, this study demonstrated that F exposure could impair the structure and epithelial barrier function of small intestine, leading to the intestinal inflammation, and pyroptosis may contribute to this damage; Furthermore, F toxicity on small intestine is reversible, and could be restored when off the F exposure environment for a certain period of time. Additionally, among the three regions of small intestine, duodenum seems more vulnerable to F exposure than jejunum and ileum.


Assuntos
Fluoretos , Piroptose , Animais , Inflamação , Intestino Delgado , Jejuno , Camundongos
9.
Sci Total Environ ; 734: 139233, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32460071

RESUMO

Arsenic (As) poisoning and its potential reproductive functional lesions are a global environmental concern. Recent studies shown that spermiogenesis tends to be a major target process in arsenic-induced male infertility, however, the underlying mechanisms are not fully illuminated. In the present study, 32 fertility related indices including sperm motility, dynamic acrosome formation and sperm flagellum during spermiogenesis in testes were evaluated in adult male mice treated with 0, 0.2, 2, and 20 ppm As2O3 via drinking water for 180 consecutive days. The results showed that out of 32 indices, 11, 25, and 29 indicators were changed statistically by 0.2-, 2-, and 20- ppm As2O3 treatment compared to the controls (0 ppm As2O3), respectively, which reveals a significant dose-dependent relationship. For details, sperm motilities were significantly decreased by 18.85%, 32.47% and 29.53% in three As2O3 treatment groups compared to the control group. Meanwhile, the ultra-structures of acrosome formation and sperm flagellum in testes have been altered by chronic arsenic exposure. Furthermore, arsenic decreased the mRNA expressions of 11 out of 13 genes associated with acrosome biosynthesis and 11 out of 12 genes related to flagellum formation in testes, particularly, down-regulated DPY19L2, AKAP3, AKAP4, CFAP44 and SPAG16 were further confirmed at the protein levels by western blotting. Taken together, chronic arsenic exposure declines male fertility by disorganizing dynamic acrosome and flagellum formation in testes. Especially, DPY19L2, AKAP3, AKAP4, CFAP44, and SPAG16 maybe the potential targets in this process. These results may offer not only a new insight to the mechanism of arsenic-induced male reproductive toxicity, but also provide a clue for the diagnosis and therapy of arseniasis.


Assuntos
Acrossomo , Proteínas de Ancoragem à Quinase A , Animais , Arsênio , Flagelos , Masculino , Proteínas de Membrana , Camundongos , Motilidade Espermática , Espermatogênese , Espermatozoides
10.
Toxicol Lett ; 326: 83-98, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32112876

RESUMO

Arsenic (As) has been implicated in causing reproductive toxicity, but the precise cellular pathway through which the As toxicity in mature F1- male mice hypothalamic-pituitary- gonadal- sperm (HPG-S) axis is induced has not well been documented. Hence, parental mice were treated to As2O3 (0, 0.2, 2, and 20 ppm in deionized water) from five weeks before mating until weaning, and the male pups from weaning to maturity. Afterward, the markers of oxidative stress, mitochondrial impairment, and autophagy as fundamental mechanisms of cytotoxicity and organ injury were evaluated. Higher As2O3 doses (2 and 20 ppm) were a potent inducer of oxidative stress, mitochondrial dysfunction, and autophagy in HPG-S axis. Concomitant with a dose-dependent increase in the number of MDC-labeled autophagic vacuoles in the HPG axis, an adverse dose-dependent effect was observed on the mean body weight, litter size, organ coefficient, and spermatogenesis. Transmission electron microscopy also revealed more autophagosomes at high As2O3 dosage. Concomitant with a dose-dependent increment in gene expression of PI3K, Atg5, Atg12, as well as protein expression of Beclin1, LC3- I, II, P62 in HPG axis tissues and Atg12 in the pituitary; a dose-dependent decrease in mTOR gene expression was recorded in the HPG tissues of mature F1-males. These observations provide direct evidence that oxidative stress-induced mitochondrial impairments and autophagic cell death, through AMPK/TSC/mTOR and LC3 related pathways, are fundamental mechanisms for As2O3- induced toxicity on the reproductive system in mature male mice offspring.


Assuntos
Arsênio/toxicidade , Autofagia/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Animais , Masculino , Camundongos
11.
J Hazard Mater ; 391: 122227, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32044640

RESUMO

Arsenic poisoning and induced potential lesion is a global concern. However, the exact mechanisms underlying its toxicity especially in male reproductive system still remain unclear. Hence, this study aimed to explore the roles of mTOR and Beclin1-Vps34/PI3K complex during As-induced-toxicity using Rapamycin (mTOR inhibitor), Beclin1 siRNA and 3-methyladenine (3-MA, Vps34/PI3K inhibitor) in testicular stromal cells. For this, mouse testis Leydig Tumor Cell lines (MLTC-1) were challenged with As2O3 (0, 3, 6 and 9 µM) exposure for 24 hs. Lyso-Tracker Red and Monodansylcadaverine (MDC) staining results depicted a significant accumulation of autophagosomes in MLTC-1 cells exposed to arsenic. Meanwhile, arsenic treatment up-regulated autophagic markers including LC3, Atg7, Beclin1 and Vps34 expressions, mTOR downstream autophagy related genes and the Beclin1-Vps34/PI3K complex associated members. Furthermore, silencing of Beclin1, and inhibition of Vps34/PI3K and mTOR altered the arsenic-induced autophagosomes formation. However, p62, the substrate protein of autophagy, was also up-regulated by arsenic administration independent on Beclin1-Vps34/PI3K complex. Altogether, our results revealed that arsenic exposure induced autophagosomes formation via regulation of the Beclin1-Vps34/PI3K complex and mTOR pathway; the blockage of autophagosomes degradation maybe due to impaired function of lysosomes. Thus, this study provides a novel mechanistic approach with respect to As-induced male reproductive toxicity.


Assuntos
Arsênio/toxicidade , Autofagia/efeitos dos fármacos , Animais , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Linhagem Celular Tumoral , Classe III de Fosfatidilinositol 3-Quinases/genética , Camundongos , Fosfatidilinositol 3-Quinases , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética
12.
Chemosphere ; 246: 125791, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31927375

RESUMO

The gut microbial compositions are easily affected by the environmental chemicals like arsenic (As) leading to dysbiosis. The dysbiosis of gut microbiome has associated with numerous diseases; among which cancer is one of the major diseases. The meticulous mechanism underlying As- altered gut microbiome, Nucleotide domine containing protein 2 (NOD2) and how altered gut microbiome disturbs the intestinal homeostasis to regulate colon cancer markers remains unclear. For this, one hundred twenty 8-week old age male mice were divided into two exposure periods (3 and 6 months), and each exposure group animals were further divided into four groups as control (received only distilled H2O), low (0.15 mg As2O3/L), medium (1.5 mg As2O3/L) and high (15 mg As2O3/L) dose (each group containing 15 mice) administrated for 3 and 6 months. The results showed that As exposure highly altered gut microbiome with a significant depletion in NOD2 in contrast to control groups. Moreover, the dendritic cells (CD11a, CD103, CX3CR1) and macrophages (F4/80) were significantly increased by As exposure. Interestingly, increased trend of inflammatory cytokines (TNF-α, IFN-γ, IL-17) and depleted anti-inflammatory cytokines (IL-10) was observed in As exposed mice. Furthermore, the colon cancer markers ß-catenin has increased while APC was arrested by As both in 3 and 6 months treated animals. Many studies reported that As altered gut microbial compositions, in this study, our results suggested that altered gut microbiome indirectly regulates colon cancer marker through immune system destruction mediated by inflammatory cytokines.


Assuntos
Arsênio/toxicidade , Poluentes Ambientais/toxicidade , Microbioma Gastrointestinal/imunologia , Animais , Arsênio/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo , Citocinas/metabolismo , Disbiose/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Intestinos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testes de Toxicidade Crônica
13.
Biol Trace Elem Res ; 193(1): 195-203, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30887282

RESUMO

The gap junction protein plays an important role in the bone formation and alteration of these proteins leading to cause bone development. Aim to determine the effects of different concentration of fluoride on gap-junctional intercellular communication (GJIC) related genes and proteins in the rats' osteoblast cells. We treated the osteoblast cells with various concentrations (0, 0.01, 0.1, 0.5, and 1.0 mM) NaF for 24 and 72 h. We used the scrape loading and dye transfer technique to research the intracellular connectivity. Moreover, the mRNA expression levels of connexin 43 (Cx43), connexin45 (Cx45), collagen I, and osteocalcin (OCN) were analyzed by qRT-PCR, the protein expression levels of connexin43 (Cx43) were analyzed by western blotting and immunofluorescence. Our results suggested that the osteoblast proliferations were decreased in the 0.5 and 1 mM NaF groups, after 24 and 72 treatments. The scrape loading and dye transfer experiment showed that the GJIC were increased in the 0.01 mM NaF group and decreased in the 0.5 and 1 mM NaF groups. In addition, the mRNA expressions of Cx43, Cx45, and OCN, and the protein expressions of Cx43 were increased in the 0.01 mM NaF group and decreased in the 0.5 and 1 mM NaF groups. In summary, these results suggest that the low concentration NaF is good for the GJIC, but the high concentration NaF damages the GJIC.


Assuntos
Comunicação Celular/efeitos dos fármacos , Fluoretos/farmacologia , Junções Comunicantes/metabolismo , Osteoblastos/metabolismo , Animais , Células Cultivadas , Conexina 43/biossíntese , Conexinas/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Osteocalcina/biossíntese , Ratos
14.
Chemosphere ; 238: 124650, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31472347

RESUMO

Arsenic (As) has become a major problem in maintaining the environment and human health due to its wide application in the production of agriculture and industry. Many studies indicate that As can affect spermatogenesis process and lower sperm quality. However, the undergoing molecular mechanism is unclear. For this, forty-eight 8-week old adult male mice were divided into four groups of twelve each, which were administrated to 0, 0.2, 2, 20 ppm As2O3 in their drinking water respectively for six months. The results showed that As treatment reduced sperm counts and increased the sperm malformation ratio of mice. Interestingly, both the amounts of round and elongated spermatids, and the ratios of spermatids elongation were decreased significantly by As exposure. Furthermore, the structure of Chromatoid Body (CB) which presents a typical nebulous shape in round spermatids after spermatogenesis arrested, and the mRNA expression levels of gene TDRD1, TDRD6 and TDRD7 related to CB were changed by arsenic. Again, the mRNA and protein expression levels of the markers DDX25 and CRM1 in haploid periods of spermatogenesis and the associated proteins HMG2, PGK2, and H4 with DDX25 regulation were declined significantly with As treatment. Taken together; it reveals that As interferes with spermatogenesis by disorganizing the elongation of spermatids. H4, HMG2 and PGK2 are regulated by DDX25 which interacts with CRM1 and may play a vital role in spermatogenesis disorder induced by As exposure, which maybe provides one of the underlying mechanisms for As-induced male reproductive toxicity.


Assuntos
Arsênio/toxicidade , Espermátides/patologia , Espermatogênese/efeitos dos fármacos , Envelhecimento , Animais , Proteínas de Ciclo Celular/genética , RNA Helicases DEAD-box/genética , Perfilação da Expressão Gênica , Masculino , Camundongos , RNA Mensageiro/metabolismo , Espermátides/efeitos dos fármacos , Espermatozoides/metabolismo
15.
Chemosphere ; 241: 124861, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31605998

RESUMO

Both arsenic (As) and fluorine (F) are toxic substances widely found in the environment, which threaten to various organs of both human and animals, especially the kidney. In this study, to investigate the individual and combined effects of arsenic (15 mg/L As2O3(III)) and fluoride (100 mg/L NaF), arsenic (15 mg/L As2O3(III)) and fluoride-arsenic (15 mg/L As2O3(III)+100 mg/L NaF) on the renal autophagy during early life, a mouse model of gestationally exposed to As and/or F was established. The results showed that the mRNA expression levels of LC3, LC3I, LC3II, Beclin-1, ULK1, Atg13 and Atg14 were significantly increased with a concomitant decrease in mTOR and Bcl-2 up on individual exposure to As and F rather than in combined (As + F) exposure. In addition, the protein expression levels of LC3-II/LC3-I, Beclin-1, and LAMP1 were significantly increased with a concomitant decrease in mTOR and Bcl-2 in the mice subjected to individual exposure than the combined exposure. Based on the results, it was observed that renal tissue of mice was highly sensitive to F than As. Moreover, the toxicity of the combined (As + F) exposure was significantly lower than that of the individual exposure, which could be attributed due to the antagonism between As and F.


Assuntos
Arsênio/toxicidade , Autofagia/efeitos dos fármacos , Exposição Ambiental , Fluoretos/toxicidade , Rim/fisiologia , Animais , Animais Recém-Nascidos , Interações Medicamentosas , Feminino , Humanos , Masculino , Troca Materno-Fetal , Camundongos , Gravidez , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Serina-Treonina Quinases TOR/metabolismo
16.
Food Funct ; 11(1): 1155-1164, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31872845

RESUMO

Bone is the main target of fluorosis, and it has been perfectly elaborated that a moderate dosage of calcium (Ca) can alleviate bone fluorosis. However, whether Ca can alleviate fluorosis through the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signaling pathway has not yet been reported. Hence, we evaluated the histopathological structure, the imbalance of the biochemical index of bone metabolism, and the expression levels of PI3K/AKT apoptosis signaling pathway-related genes in rats treated with sodium fluoride (NaF, F) and/or calcium carbonate (CaCO3) for 120 days. Our results suggest that 100 mg L-1 NaF induced histopathological injury as alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (StrACP) activity increased, with a decrease in the serum Ca levels (p < 0.05). Moreover, the results of qRT-PCR and western blotting showed that F increased the expression levels of transglutaminase 2 (TGM2), focal adhesion kinase (FAK), PI3K, AKT, forkhead box O1 (Foxo1), Bcl-2 interacting mediator of cell death (BIM), Bcl2-associated x protein (Bax) and Caspase 3 (p < 0.05, p < 0.01). It also decreased the expression of AnnexinA5 (Anxa5), 3'-phosphoinositide-dependent kinase 1 (PDK1) and B-cell lymphoma-2 (Bcl-2) (p < 0.05, p < 0.01), which finally activated the PI3K/AKT pathway. On the other hand, CaCO3 supplementation reversed the histopathological injury along with the levels of ALP, StrACP and serum Ca, alleviating the gene expression levels of PI3K/AKT pathway-related markers. Altogether, we can conclude that CaCO3 supplementation mitigated F-induced bone damage via the PI3K/AKT signaling pathway.


Assuntos
Osso e Ossos/efeitos dos fármacos , Cálcio/metabolismo , Fluoretos/efeitos adversos , Transdução de Sinais , Animais , Apoptose , Osso e Ossos/patologia , Intoxicação por Flúor/terapia , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley
17.
Environ Pollut ; 256: 113438, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31672359

RESUMO

It is very important to explore the potential harm and underlying mechanism of fluoride due to the extensive distribution and the significant health risks of fluoride in environment. The objective of this study to investigate whether fluoride can induce mitochondrial impairment and mitophagy in testicular cells. For this, 40 male mice were randomly divided into four groups treated with 0, 0.6, 1.2, 2.4 mM NaF deionized water, respectively, for 90 days continuously. The results showed that mitophagy was triggered by F in testicular tissues, especially in the Leydig cells by transmission electron microscopy and mitophagy receptor PHB2 locations by immunofluorescence. Furthermore, TM3 Leydig cells line was employed and treated with 0, 0.125, 0.25, and 0.5 mM NaF for 24 h. The mitochondrial function indicators and mitophagy maker PHB2, COX IV and regulator PINK1 in transcript and protein levels in Leydig cells were examined by the methods of qRT-PCR, western blotting, and immunofluorescence co-localization. The results showed that fluoride decreased the mitochondrial membrane potential with a concomitant increase in the number of lysosomes. Meanwhile, fluoride exposure also increased the expressions of PINK1 and PHB2 in TM3 Leydig cells. These results revealed that fluoride could induce mitochondrial impairment and excessive PINK1/Parkin-mediated mitophagy in testicular cells, especially in Leydig cells, which could contribute to the elucidation of the mechanisms of F-induced male reproductive toxicity.


Assuntos
Poluentes Ambientais/toxicidade , Fluoretos/toxicidade , Células Intersticiais do Testículo/fisiologia , Mitofagia , Proteínas Quinases/metabolismo , Animais , Fluoretos/metabolismo , Humanos , Células Intersticiais do Testículo/metabolismo , Masculino , Potencial da Membrana Mitocondrial , Camundongos , Mitocôndrias/metabolismo , Ubiquitina-Proteína Ligases
18.
J Agric Food Chem ; 67(48): 13333-13343, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31703480

RESUMO

Fluoride (F) widely exists in the water and food. Recent studies reported that F induced testicular toxicity via inflammation reaction. This study was aimed to explore the mechanism of F-induced inflammation in testis. 100 healthy male mice (BALB/cJ strain) were randomly divided into five groups including: control, experimental autoimmune orchitis (EAO), and three F groups (25, 50, and 100 mg/L sodium fluoride (NaF)). After 150 d, the results showed a significant increase in testicular cytokines levels including of IL-17A, IL-6, IFN-γ, and TNF-α in NaF and EAO groups compared with control group. Interestingly, the presence of specific antisperm autoantibodies in antitesticular autoantibodies and the notable recruitment of immunocyte (T cells and dendritic cells) were also observed in NaF and EAO groups. In addition, findings showed that in NaF and EAO groups macrophages and T cells both significantly secreted IL-17A, and the protein and mRNA levels of cytokines (IL-6 and TGF-ß) were significantly increased. From these results, it can be concluded that autoimmune orchitis and IL-17A are implicated in F-induced testicular inflammation.


Assuntos
Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Fluoretos/efeitos adversos , Interleucina-17/imunologia , Orquite/imunologia , Testículo/imunologia , Animais , Doenças Autoimunes/genética , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Humanos , Interleucina-17/genética , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Orquite/induzido quimicamente , Orquite/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Testículo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
19.
J Agric Food Chem ; 67(37): 10285-10295, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31443611

RESUMO

Fluoride (F) is capable of promoting abnormal proliferation and differentiation in primary cultured mouse osteoblasts (OB cells), although the underlying mechanism responsible remains rare. This study aimed to explore the roles of wingless and INT-1 (Wnt) signaling pathways and screen appropriate doses of calcium (Ca2+) to alleviate the sodium fluoride (NaF)-induced OB cell toxicity. For this, we evaluated the effect of dickkopf-related protein 1 (DKK1) and Ca2+ on mRNA levels of wingless/integrated 3a (Wnt3a), low-density lipoprotein receptor-related protein 5 (LRP5), dishevelled 1 (Dv1), glycogen synthase kinase 3ß (GSK3ß), ß-catenin, lymphoid enhancer binding factor 1 (LEF1), and cellular myelocytomatosis oncogene (cMYC), as well as Ccnd1 (Cyclin D1) in OB cells challenged with 10-6 mol/L NaF for 24 h. The demonstrated data showed that F significantly increased the OB cell proliferation rate. Ectogenic 0.5 mg/L DKK1 significantly inhibited the proliferation of OB cells induced by F. The mRNA expression levels of Wnt3a, LRP5, Dv1, LEF1, ß-catenin, cMYC, and Ccnd1 were significantly increased in the F group, while significantly decreased in the 10-6 mol/L NaF + 0.5 mg/L DKK1 (FY) group. The mRNA expression levels of Wnt3a, LRP5, ß-catenin, and cMYC were significantly decreased in the 10-6 mol/L NaF + 2 mmol/L CaCl2 (F+CaII) group. The protein expression levels of Wnt3a, Cyclin D1, cMYC, and ß-catenin were significantly increased in the F group, whereas they were decreased in the F+CaII group. However, the mRNA and protein expression levels of GSK3ß were significantly decreased in the F group while significantly increased in the F+CaII group. In summary, F activated the canonical Wnt/ß-catenin pathway and changed the related gene expression and ß-catenin protein location in OB cells, promoting cell proliferation. Ca2+ supplementation (2 mmol/L) reversed the expression levels of genes and proteins related to the canonical Wnt/ß-catenin pathway.


Assuntos
Cálcio/metabolismo , Fluoretos/efeitos adversos , Osteoblastos/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Suplementos Nutricionais/análise , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Osteoblastos/classificação , Osteoblastos/metabolismo , Proteínas Wnt/genética , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética
20.
J Agric Food Chem ; 67(39): 10832-10843, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31464433

RESUMO

Excessive fluoride mainly causes skeletal lesions. Recently, it has been reported that an appropriate level of calcium can alleviate fluorosis. However, the appropriate concentration and mechanism of calcium addition is unclear. Hence, we evaluated the histopathology and ultrastructure, DNA fragmentation, hormonal imbalances, biomechanical levels, and expression of apoptosis-related genes after treating the rats with 150 mg/L NaF and different concentrations of CaCO3. Our results suggested that NaF induced the histopathological and ultrastructural injury, with a concomitant increase in the DNA fragmentation (P < 0.05) and serum OC (17.5 ± 0.89 pmoL/L) at 120 days. In addition, the qRT-PCR and western blotting results indicated that NaF exposure upregulated the mRNA and protein expression of Bax, Calpain, Caspase 12, Caspase 9, Caspase 7, Caspase 3, CAD, PARP, and AIF while downregulated Bcl-2 (P < 0.01) and decreased the bone ultimate load by 27.1%, the ultimate stress by 10.1%, and the ultimate deformity by 23.3% at 120 days. However, 1% CaCO3 supplementation decreased the serum OC (14.7 ± 0.65 pmoL/L), bone F content (P < 0.01), and fracture and breakage of collagen fibers and changed the expression of endoplasmic reticulum pathway-related genes and proteins at 120 days. Further, 1% CaCO3 supplementation increased the bone ultimate load by 20.9%, the ultimate stress by 4.89%, and the ultimate deformity by 21.6%. In summary, we conclude that 1% CaCO3 supplementation alleviated fluoride-induced bone damage by inhibiting endoplasmic reticulum stress and mitochondrial dysfunction.


Assuntos
Osso e Ossos/efeitos dos fármacos , Cálcio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fluoretos/toxicidade , Mitocôndrias/efeitos dos fármacos , Animais , Osso e Ossos/metabolismo , Caspases/genética , Caspases/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley
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